Cellular early response genes are a class of genes whose transcription is activated within minutes of exposure of cells to stimuli. When quiescent cells are stimulated, the early-response genes are rapidly induced. These genes alter target gene expression by coupling short-term signals induced by extracellular stimuli to long-term changes in cellular phenotype. They encode proteins that induce phenotypic alterations by modulating the transcription rates of genes, and have been shown to have critical roles in the control of growth and differentiation (Lau, L. And Nathans, D. (1987) Proc. Natl. Acad. Sci. 84: 1182-1186).
Extracellular stimuli which induce early response genes include growth factors, phorbol esters, okadaic acid, protein synthesis inhibitors, toxins, and abrupt changes in temperature, pH, and oxygen. The stimulus activates cell surface receptors and membrane bound molecules which initiate signaling cascades that induce the transcription of early response genes. These early response genes include the genes for cytokines; fos, myc, jun, the edg-1 receptor, and nuclear receptors, all of which have roles in cellular proliferation and differentiation.
The edg-1 receptor is an immediate-early response gene that has been characterized in rats and humans and is induced by stimuli that initiate cellular differentiation. The edg-1 gene product is a G-protein-coupled receptor classified as an orphan receptor because its' ligand is unknown. It shares features with other seven transmembrane proteins including seven hydrophobic domains which span the plasma membrane and form a bundle of antiparallel .alpha. helices. Stimulation of these receptors by agonists activates the receptor and allows it to interact with an intracellular G-protein complex. The G protein complex activates a variety of second messenger molecules which regulate signaling pathways and modulate cellular responses (Lee, M. J. et al (1996) J. Biol. Chem. 271: 11272-11279).
The human edg-1 receptor was first isolated by Hla, T. and Maciag, T. (1990, J. Biol. Chem. 265: 9308-9313) when they were screening phorbol 12-myristate 13-acetate (PMA) treated endothelial cells for induced early gene transcripts involved in cell differentiation. Endothelial cell differentiation is a key factor in the initiation of angiogenesis. This is a process by which new vascular networks are formed from pre-existing capillaries and is necessary for growth, tissue remodeling, and wound repair. Physiologically, it is essential for embryogenesis, tissue and organ development, ovulation, and corpus luteum formation. In addition, it occurs during the progression of various pathological conditions such as diabetic retinopathy, rheumatoid arthritis, occlusive vascular diseases, and cancers, where angiogenesis provides the nutrients and oxygen for growth of solid tumors. PMA is a tumor promoter which alters the growth of endothelial cells in vitro and stimulates their differentiation into capillary-like tubules. Many of the early endothelial cell genes induced by PMA treatment have a role in cell differentiation and, as such, determine the molecular events involved in the control of cellular growth and differentiation.
The discovery of new edg-1-like receptor and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of cancers and disorders of cellular growth and differentiation.